Molecular Cancer Therapeutics最新文献

{"title":"Depleting the action of EZH2 through PI3K-mTOR inhibition to overcome metastasis and immunotherapy resistance in triple-negative breast cancer.","authors":"Michelle Melino, Wen Juan Tu, Helle Bielefeldt-Ohmann, Martina Proctor, Taniya Ahuja, John Vandermeide, Amanda L Bain, Gahyathiri Nallan, Sal Lee Goh, Thiru Prasanna, Jane E Dahlstrom, Mariska Miranda, Ramesh Kumar Choudhary, Aravind Anandam, Sumit Chaudhary, Jonathan T Seal, Debottam Sinha, Shaoqian Zhang, Tam Hong Nguyen, Sriganesh Srihari, Gunter Hartel, Amy Ives, Laeeq Malik, Desmond Yip, Michelle Nottage, Melissa Eastgate, Sudha Rao","doi":"10.1158/1535-7163.MCT-24-0693","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0693","url":null,"abstract":"<p><p>Almost half of patients with triple-negative breast cancer (TNBC) develop distant metastases, heralding unfavorable outcomes. Here we provide novel insights into the contribution of the PI3K-mTOR pathway to the TNBC phenotypes that promote growth, migration, metastasis, and therapy resistance. Specifically, we demonstrate that dual targeting of PI3K and mTOR but not PI3K alone inhibits cancer cell proliferation and migration in vitro. Dual PI3K-mTOR inhibition with paxalisib not only promotes a favorable mesenchymal to epithelial phenotype but also inhibits signatures associated with MICs, including the highly aggressive CSC phenotype, persister cancer cell phenotype (p65, FOXQ1, NRF2, NNMT), and a cancer drug resistance signature (ABCB5, SNAIL, ALDH1). In vivo, paxalisib overcomes immunotherapy resistance to reduce primary tumor burden, circulating tumor cells, and direct and indirect indicators of metastasis with a favorable toxicity profile. Gene expression and spatial analyses show that paxalisib profoundly affects the immune microenvironment in tumors, reducing adaptive immune phenotypes associated with immunotherapy resistance (exhausted T cells, Tregs) and pro-tumor innate immune populations such as mast cells. PI3K-mTOR blockade acts upstream of EZH2, impacting both the classical repressive catalytic p85β-EZH2-H27ME3 and active EZH2-NFκB pathways. Our data suggest that dual targeting of the PI3K-mTOR pathway disrupts both the catalytic and non-catalytic axes of EZH2 to inhibit metastasis and enhance cancer immune visibility, potentially increasing the utility of immunotherapy in resistant individuals.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical Evaluation of PTK7-Targeted Radionuclide Therapy.","authors":"Kim Lindland, Sara Westrøm, Srdan M Dragovic, Ruth Gong Li, Marion Masitsa Malenge, Betty Ho, Asta Juzeniene, Tina Bjørnlund Bønsdorff","doi":"10.1158/1535-7163.MCT-24-1060","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-1060","url":null,"abstract":"<p><p>Protein tyrosine kinase 7 (PTK7), a receptor found in tumor-initiating cells, is expressed in various malignancies, including ovarian cancer. While PTK7 has been explored as a target for antibody-drug conjugates, this study is the first to investigate its potential for targeted radionuclide therapy. We developed a murine monoclonal IgG1 antibody (mOI-1) using hybridoma technology and generated a chimeric version (chOI-1) with human IgG1 constant regions. A cell-based screening approach using a library of 6100 cell surface proteins identified PTK7 as the target, confirmed by flow cytometry and surface plasmon resonance analyses. Immunohistochemistry showed strong PTK7 expression in ovarian cancer tissues, and in vitro studies demonstrated specific binding and internalization of OI-1 in the ovarian cancer cell line SKOV-3-luc. Biodistribution studies using 177Lu-DOTA-mOI-1 injected intravenously in xenograft mice with subcutaneous SKOV-3-luc revealed high tumor uptake and retention. Therapeutic efficacy was assessed by intraperitoneal treatment with 212Pb-TCMC-chOI-1 in an intraperitoneal xenograft model, showing significant tumor growth inhibition compared to non-radioactive controls. This study provides the first investigation of a PTK7-targeting antibody (OI-1) as an antibody-radionuclide conjugate (212Pb-labeled) in a preclinical model of intraperitoneal ovarian cancer. These results support further investigation of OI-1 as a candidate for targeted radionuclide therapy in PTK7-expressing cancers.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ANXA1 binds and stabilizes EGFR to promote nasopharyngeal carcinoma radioresistance.","authors":"Ting Zeng, Ding Xiao, Wei Zhu, Di Wu, Hong Yi, Wei Huang, Shan-Shan Lu, Zheng-Zheng Yu, Qi Wen, Yun-Xi Peng, Li Yuan, Zhi-Qiang Xiao, Jinwu Peng","doi":"10.1158/1535-7163.MCT-24-0944","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0944","url":null,"abstract":"<p><p>Radioresistance is a serious obstacle to successful nasopharyngeal carcinoma (NPC) treatment. ANXA1 is associated with EGFR and is involved in EGFR-promoting tumors, but mechanism of ANXA1-stabilizing EGFR and its effect on NPC radioresistance are unclear. Here, we report that ANXA1 competes with E3 ubiquitin ligase Cbl for binding EGFR, and increases its stability by inhibiting Cbl-mediated EGFR ubiquitination degradation in NPC cells. ANXA1 increases in vitro and in vivo NPC cell radioresistance by stabilizing EGFR. Expression levels of ANXA1 and EGFR are positively correlated in NPC tissues, and are significantly higher in the radioresistant NPC tissues than in the radiosensitive NPC tissues. The NPC patients with high expression of both proteins have poorer overall survival and disease free survival relative to patients with high expression of one protein alone, and a combination of ANXA1 and EGFR predicts NPC radiosensitivity superior to individual protein. Based on the amino acid residues of ANXA1 responsible for binding EGFR, we develop a nine amino acid-long ANXA1-derived peptide (HDMNKVLDL), which disrupts the connection of ANXA1 with EGFR, successfully downregulates EGFR expression, and dramatically increases NPC cell radiosensitivity in vitro and in mice. Our findings suggest that ANXA1 promotes NPC radioresistance via binding and stabilizing EGFR, and present a strategy for targeting EGFR degradation and NPC radiosensitizaton with a peptide.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a Novel Bifunctional Anti-CD47 Fusion Protein with Improved Efficacy and a Favorable Safety Profile.","authors":"Sittana Matar, Seham Skah, Liza E Diomande, Tim Buss, Hanne R Hagland, Ajay Yadav, Rune J Forstrøm, Bjørn Dalhus, Kjetil Hestdal, Rolf D Pettersen, Nina Richartz","doi":"10.1158/1535-7163.MCT-24-0917","DOIUrl":"10.1158/1535-7163.MCT-24-0917","url":null,"abstract":"<p><p>Therapeutic anti-CD47 monoclonal antibodies (mAbs) are designed to block the CD47-SIRPα checkpoint and promote immune-mediated recognition and elimination of cancer cells. However, current anti-CD47 mAbs have limitations, including off-tumor toxicity and reduced effectiveness in advanced cancers. Additionally, CD47 serves as a death receptor that mediates programmed cancer cell death (PCCD), a mechanism that has not been fully explored in current therapies. In this study, we introduce CO-001, a chimeric bifunctional IgG4 mAb, and its optimized variant CO-005, a bivalent humanized single-chain fragment variable-fragment crystallizable fusion protein. Both CO-001 and CO-005 promoted phagocytosis and PCCD. CO-005, specifically engineered to overcome the safety limitations associated with anti-CD47 antibodies, demonstrates a superior hematologic safety profile in vitro and ex vivo compared with benchmark anti-CD47 antibodies. Notably, CO-005 exhibited no binding to red blood cells, limited binding to white blood cells, and showed no hemagglutination activity. In preclinical models, CO-005 demonstrated potent antitumor activity in B-cell precursor acute lymphoblastic leukemia and Raji lymphoma xenograft models through the dual action of PCCD induction and enhancement of phagocytosis. The ability of CO-005 to trigger strong PCCD while preserving conventional immune responses provides a novel and promising approach for CD47-targeted cancer therapy. Its favorable safety profile, observed in both in vitro and ex vivo studies, positions CO-005 as a promising candidate with potential therapeutic advantages over existing anti-CD47 treatments.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"816-827"},"PeriodicalIF":5.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"177Lu-Labeled Antibody-Drug Conjugate: A Dual-Mechanistic Treatment Modality in Solid Tumors.","authors":"Aiko Yamaguchi, Chisato M Yamazaki, Yasuaki Anami, Summer Y Y Ha, Wei Xiong, Robert T Ta, Ningyan Zhang, H Charles Manning, Zhiqiang An, Kyoji Tsuchikama","doi":"10.1158/1535-7163.MCT-24-0254","DOIUrl":"10.1158/1535-7163.MCT-24-0254","url":null,"abstract":"<p><p>To explore the potential of site-selectively radiolabeled antibody-drug conjugates (ADC) against solid tumors, we constructed and evaluated radiolabeled ADCs equipped with lutetium-177 (177Lu) and a membrane-permeable antimitotic agent. Site-selective 177Lu-labeled ADCs [anti-trophoblast cell-surface antigen 2 (TROP2) 177Lu-DTPA ADCs or anti-HER2 177Lu-DO3A ADCs], a 177Lu-labeled homogeneous radioimmunoconjugate (homogeneous RIC), and 177Lu-labeled conventional RIC (heterogeneous RIC) were constructed. We confirmed that 177Lu-labeled ADCs and the homogeneous RIC were obtained with high homogeneity and defined chelator/payload-to-antibody ratios. Next, we performed biodistribution studies and treatment efficacy studies in xenograft mouse models bearing orthotopic breast tumors. Compared with the heterogeneous RIC, the 177Lu-DTPA TROP2 ADC and anti-TROP2 homogeneous RIC showed significantly improved radioactivity accumulation in the TROP2-expressing JIMT-1 tumor (P < 0.01 at 72 hours). In the therapeutic study, 177Lu-DTPA TROP2 ADC (5 MBq; 1.5 mg/kg) suppressed tumor growth significantly more than did the anti-TROP2 homogeneous RIC (5 MBq, P = 0.0068). Anti-HER2 177Lu-DO3A ADC (5 MBq; 3.0 mg/kg) demonstrated greater in vivo treatment efficacy over monomethyl auristatin E DAR 2 HER2 ADC (3.0 mg/kg) monotherapy, anti-HER2 homogeneous RIC (5 MBq) monotherapy, and the combination of monomethyl auristatin E DAR 2 HER2 ADC and anti-HER2 homogeneous RIC at matched payload and radioactivity doses in a refractory breast tumor model displaying heterogeneous HER2 expression. These results suggest that site-selectively 177Lu-labeled ADCs are effective in treating refractory tumors, including those with heterogeneous antigen expression, and warrant further exploration as a promising single-agent, dual-mechanistic treatment modality for solid tumors.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"907-919"},"PeriodicalIF":5.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA-PK Inhibition Shows Differential Radiosensitization in Orthotopic GBM PDX Models Based on DDR Pathway Deficits.","authors":"Sonja Dragojevic, Emily J Smith, Michael S Regan, Sylwia A Stopka, Gerard Baquer, Zhiyi Xue, Wenjuan Zhang, Margaret A Connors, Jake A Kloeber, Zeng Hu, Katrina K Bakken, Lauren L Ott, Brett L Carlson, Danielle M Burgenske, Paul A Decker, Shulan Tian, Shiv K Gupta, Daniel J Laverty, Jeanette E Eckel-Passow, William F Elmquist, Nathalie Y R Agar, Zachary D Nagel, Jann N Sarkaria, Cameron M Callaghan","doi":"10.1158/1535-7163.MCT-24-0003","DOIUrl":"10.1158/1535-7163.MCT-24-0003","url":null,"abstract":"<p><p>Glioblastoma (GBM) remains one of the most therapy-resistant malignancies with frequent local failures despite aggressive surgery, chemotherapy, and ionizing radiation (IR). Small molecule inhibitors of DNA-dependent protein kinase (DNA-PKi) are potent radiosensitizers currently in clinical trials. Determining which patients may benefit from radiosensitization with DNA-PKi is critical to avoid unnecessary increased risk of normal tissue toxicity. In this study, we used GBM patient-derived xenografts (PDX) in orthotopic murine models to study the relationship between molecular features, pharmacokinetics, and the radiosensitizing potential of the DNA-PKi peposertib. We show that peposertib radiosensitizes established and PDX GBM lines in vitro at 300 nmol/L and above, with a significant increase in radiosensitization by maintaining post-IR exposure for >12 hours. Radiosensitization by peposertib is mediated by catalytic inhibition of DNA-PK, and knockdown of DNA-PK by short hairpin RNA (shRNA) largely abolished the radiosensitizing effect. Peposertib decreased auto-phosphorylation of DNA-PKcs after IR in a dose-dependent manner with a delay in resolution of γH2AX foci at 24 hours. The addition of peposertib to IR significantly increased survival in GBM120 orthotopic xenografts, but not in GBM10. There was no difference in plasma or average tumor concentrations of peposertib in the two cohorts. Although the mechanism underpinning this discordant effect in vitro versus in vivo is not clear, there was an association for greater sensitization in TP53 mutant lines. Transfection of a dominant-negative TP53 mutant in baseline TP53 wild-type GBM lines significantly delayed growth and decreased nonhomologous end joining efficiency (but not homologous recombination), after peposertib exposure. See related commentary by Buchsbaum, p. 840.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"859-869"},"PeriodicalIF":5.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12014860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blockade of the PGE2 Pathway Inhibits the Growth of PTEN-Deficient HNSCC Tumors.","authors":"Jacqueline P Nguyen, Shorook Na'ara, Liam C Woerner, Nathan K VanLandingham, Marius Hoerner, Rodell T Santuray, Kelly Blum, Mi-Ok Kim, Daniel E Johnson, Jennifer R Grandis","doi":"10.1158/1535-7163.MCT-24-0604","DOIUrl":"10.1158/1535-7163.MCT-24-0604","url":null,"abstract":"<p><p>Increased PI3K signaling as a result of PIK3CA mutation or amplification or decreased expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is one of the most common alterations in head and neck squamous cell carcinoma (HNSCC). PTEN negatively regulates PI3K signaling and its downstream effectors including COX2. COX2 mediates the synthesis of prostaglandin E2 (PGE2) which contributes to immunosuppression in the tumor microenvironment. PGE2 also binds to one or more EP receptors (EP1-EP4) and promotes the growth of tumor cells via activation of EP2 and EP4. However, the role of PGE2 in PTEN-deficient HNSCC is incompletely understood. In this study, we assessed PGE2 signaling in PTEN-deficient HNSCC and evaluated the effect of aspirin or TPST-1495, a dual EP2/EP4 antagonist, on the growth of PTEN knockout and PIK3CA-altered HNSCC tumors in immunocompetent mice. Our results demonstrated that aspirin selectively inhibits the growth of PTEN knockout HNSCC tumors. TPST-1495 inhibited tumor growth and substantially increased the antitumor activity of the immune checkpoint inhibitor anti-PD1. To date, there are no FDA-approved therapies for PI3K pathway-altered HNSCC. Our findings suggest that NSAIDs demonstrate antitumor activity in PTEN-deficient or PI3K-altered tumors whereas EP2/EP4 targeting may augment FDA-approved anti-PD1 therapy in HNSCC.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"931-941"},"PeriodicalIF":5.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Broadening the Therapeutic Window of ADCs Using Site-Specific Bioconjugation Showcased by an MMAE-Containing Peptide Linker in a CD79b-Targeting ADC.","authors":"Philipp Probst, Isabella Attinger-Toller, Romain Bertrand, Ramona Stark, Roger Santimaria, Bernd Schlereth, Dragan Grabulovski, Philipp René Spycher","doi":"10.1158/1535-7163.MCT-24-0983","DOIUrl":"10.1158/1535-7163.MCT-24-0983","url":null,"abstract":"<p><p>The limitations of first-generation antibody-drug conjugate (ADC) technologies include suboptimal stability and efficacy, poor safety profiles, and challenging manufacturing processes. In this study, we describe an anti-CD79b-monomethyl auristatin E (MMAE) ADC generated using a novel peptide-based linker technology that allows for site-specific linker-payload conjugation to native antibodies in only one step. The ADC comprises native polatuzumab as the targeting antibody and a linker-payload consisting of a RKAA-peptide linker and MMAE. We compared our anti-CD79b-RKAA-MMAE ADC with polatuzumab vedotin (PV), the FDA-approved ADC for diffuse large B-cell lymphoma. In the clinic, PV shows significant instability in circulation, leading to strong and dose-limiting side effects, including neutropenia and peripheral neuropathy. The anti-CD79b-RKAA-MMAE ADC showed optimal biophysical properties with a well-defined drug-to-antibody ratio of 2. It demonstrated potent cytotoxicity in multiple cancer cell lines and was very stable in mouse, cynomolgus monkey, and human sera. The anti-CD79b-RKAA-MMAE conjugate showed equal antitumor efficacy at half the payload dose compared with PV in different xenograft models. At equal MMAE concentrations, greater tumor growth inhibition and a considerably longer duration of response were observed. Ultimately, the highest nonseverely toxic dose of 30 mg/kg was determined in a 4-week repeat-dose toxicology study in rats, which is a 3-fold higher ADC dose than reported for PV. In summary, the data show that our novel site-specific bioconjugation technology enabled the generation of an anti-CD79b-RKAA-MMAE ADC with highly favorable biophysical properties and a greatly improved therapeutic index by a factor of 4 to 6 compared with PV. The ADC may therefore represent a safe and efficacious alternative for patients with diffuse large B-cell lymphoma.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"803-815"},"PeriodicalIF":5.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NOC2L Promotes Paclitaxel Resistance in Various Types of Ovarian Cancers by Decreasing NDUFA4 through Histone Acetylation Suppression.","authors":"Hao Gu, Suwan Qi, Jiaying Chen, Hongqin Wu, Jianjuan Xu, Yaling Feng","doi":"10.1158/1535-7163.MCT-24-0512","DOIUrl":"10.1158/1535-7163.MCT-24-0512","url":null,"abstract":"<p><p>Ovarian cancer is a common malignant tumor in the female reproductive system. Paclitaxel resistance is the primary cause of treatment failure in patients with ovarian cancer. Therefore, elucidating the mechanisms by which ovarian cancer develops paclitaxel resistance is crucial for achieving better therapeutic outcomes. This study analyzed data from the GSE50831 dataset (the response of 21 ovarian cancer cell lines to paclitaxel), the GSE26193 dataset (the progression of 107 patients with ovarian cancer), and the Ovarian Cancer Genome Atlas. Key differentially expressed genes were selected through intersection analysis, least absolute shrinkage and selection operator, and multivariate Cox regression analysis. Experiments were conducted to validate the candidate gene, NOC2L, and explore its role in the development of paclitaxel resistance in ovarian cancer cells. Data from these datasets showed that NOC2L was upregulated in all ovarian cancer cell lines after paclitaxel treatment, and this upregulation was associated with poorer patient progression. Both loss- and gain-of-function experiments confirmed that NOC2L promotes ovarian cancer cell resistance to paclitaxel. The Ovarian Cancer Genome Atlas dataset showed that NOC2L is negatively correlated with the NADH:ubiquinone oxidoreductase core subunit family (NDUF) proteins: NDUFB4, NDUFA1, NDUFS4, NDUFB1, NDUFA2, NDUFA4, and MT-ND3. Studies have revealed that NOC2L decreases the expression of NDUF proteins, particularly NDUFA4, by suppressing histone acetylation, resulting in a remodeling of energy metabolism toward aerobic glycolysis. Collectively, NOC2L inducing energy metabolism to aerobic glycolysis is a consistent mechanism in various ovarian cancer cells resistant to paclitaxel. Hence, NOC2L is a promising target to improve the sensitivity of ovarian cancer cells to paclitaxel.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"942-956"},"PeriodicalIF":5.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Three Articles from the NCI's Preclinical Chemoradiotherapy Testing Consortium.","authors":"Jeffrey C Buchsbaum","doi":"10.1158/1535-7163.MCT-24-0234","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0234","url":null,"abstract":"<p><p>In this issue of MCT, three articles from the NCI's Preclinical Chemoradiotherapy Testing Consortium (PCRTC) are presented that each demonstrates a story of success. Each cooperative agreement team's results are briefly summarized, and both the importance and the limitations of these studies are discussed. These preclinical studies used agents from the Cancer Therapy Evaluation Program portfolio to develop the foundation for translation into clinical trials. The structure of these studies was based on the prior work of the PCRTC that laid out the methodology for optimizing potential translation. Rigor and reproducibility have been a continuing focus of the PCRTC, with a key feature being the requirement for dose measurement and calibration to be traceable to national standards. Through the application of the consortium's prior work establishing the standards for translation, each group generated promising data with high translational potential. See related article by Valvo et al., p. 843 See related article by Dragojevic et al., p. 859 See related article by Lu et al., p. 920.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":"24 6","pages":"840-842"},"PeriodicalIF":5.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}